Mutations in hippocalcin and autosomal recessive dystonia: a role for perturbed calcium signaling?


The advent of next-generation sequencing (NGS) has resulted in an expansion in the number of dystonia-causing genes identified. Confirmed genes for isolated dystonia include TOR1A (DYT1), THAP1 (DYT6), and GNAL (DYT25). Several recently identified genes, including TUBB4 (DYT4), CIZ1 (DYT23), and ANO3 (DYT24), probably require further confirmation. Moreover, forms of primary isolated dystonia with a presumed autosomal-recessive inheritance pattern have been lumped together under the banner of “DYT2” or “DYT2-like”, without a specific gene or linkage interval being identified. Recently, Charlesworth et al. reported a new dystonia gene as a possible cause of DYT2 dystonia. They investigated a consanguineous Sephardic Jewish family with three siblings affected by primary isolated dystonia. The onset of dystonia was in the first decade of life, becoming generalized over time but remaining most marked in the upper limbs and craniocervical region. A combination of homozygosity mapping and whole-exome sequencing identified a homozygous mutation in the hippocalcin (HPCA) gene as the cause of disease. This gene encodes a neuronal calcium sensor protein found almost exclusively in the brain and at particularly high levels in the striatum. Subsequently, compound-heterozygous mutations in HPCA were also identified in a Sri Lankan kindred affected by autosomal-recessive isolated dystonia. The investigators used Hpca-knockdown neuronalastrocytic cocultures to demonstrate that hippocalcin deficiency leads to a pattern of severely altered neuronal responses to physiological stimuli. This suggests that HPCA deficiency might inhibit voltage-dependent Ca channels or modify the mechanism of maintaining membrane potential, thus affecting the cellular response to membrane depolarization. Additional genetic screening studies would be useful to determine the mutation frequency and characterize the clinical phenotype, perhaps including patients from geographical regions with high rates of consanguinity. Further laboratory studies are also required to define the role of hippocalcin and to identifying downstream interactors of this protein.

DOI: 10.1002/mds.26261

Cite this paper

@article{Kumar2015MutationsIH, title={Mutations in hippocalcin and autosomal recessive dystonia: a role for perturbed calcium signaling?}, author={Kishore Raj Kumar}, journal={Movement disorders : official journal of the Movement Disorder Society}, year={2015}, volume={30 7}, pages={911} }